Activation of members of the tyrosine kinase family of oncogenes have been implicated in the genesis of a large proportion of sporadic human breast cancers. Although considerable knowledge has been obtained regarding the mechanism by which this class of oncogenes induces malignant transformation, there are still significant gaps in our understanding the relative contribution of particular signaling pathways to mammary tumorigenesis and metastasis. This project is focused on elucidating the role of the PI-3K and its coupled signaling pathways in mammary tumor progression. The first experimental goal of the proposal is to asses the role of PI-3K in mammary tumor progression. To accomplish this we will derive transgenic mice that coexpress a constitutively active version of the PI-3K and either ErbB-2 or mutant PyV oncogenes in the mammary epithelium. Because the activation of PI-3K can result in stimulation of a number of downstream signaling molecules including the Akt and Integrin linked serine kinases, the second major objective of the proposal is assess the relative contribution of these signaling pathways to mammary tumor progression. To accomplish this, we will derive transgenic mice that co-express constitutively activated versions of the various Akt family members with either activated ErbB-2 or PyV mT oncogenes too determine if elevated expression of the three Akt family members can modulate tumor progression in these defined transgenic tumor models. Conversely, we will assess whether mnammary epithelial expression of a dominant negative version of Akt can interfere with tumor progression in these transgenic tmor models. Another potential target of PI-3K signaling pathway is the integrin linked kinase (ILK). To determine whether the function of ILK is required for tumor progression in either ErbB-2 or PyV mT transgenic strains, we plan to use the Cre/LOX recombination system to create a mammary specific knockout of ILK in these transgenic tumor models. The results of these studies will provide important insight into the role of these PI-3K coupled signaling pathways in mammary tumorigenesis and metastasis.